1. Field of the Invention
The present invention relates to a ‘second generation of ACOMP’ (Automatic Continuous Online Monitoring of Polymerization reactions). The present document also sets out principles and uses, for the first time, of ACOMP (U.S. Pat. No. 6,653,150) coupled to SMSLS (simultaneous multiple sample light scattering, a Reed patent (U.S. Pat. No. 6,618,144) held by Tulane), and expands the uses of SMSLS through specific design changes.
The present invention is particularly suited to monitoring special characteristics of polymers and colloids as they evolve during reactions, such as polymer synthesis or postpolymerization modification reactions. Special characteristics include the polymers' and/or colloids' ability to respond to environmental stimuli, such as temperature, light, and solution characteristics such as pH, ionic strength, presence of specific other substances, such as toxins, drugs, surfactants, and other molecules, including other polymers, colloids, and nanostructures, their ability to go through structural changes, such as conformational collapse, their ability to self-assemble into supramolecular structures, and their ability to encapsulate and bind other agents, and to release them. The use of the present invention in conjunction with multiple similar detectors in some contexts can allow determination of polymer and/or colloid phase behavior during reactions, and how the phase behavior changes during reactions.
Although the samples are prepared automatically and continuously, detection can be intermittent. Interrupted, chromatographic detection, such as size exclusion chromatography, can be used. A recent publication the inventor and his colleagues made in this area is: “Simultaneous continuous, non-chromatographic monitoring and discrete chromatographic monitoring of polymerization reactions”, Alina M. Alb, Michael F. Drenski, Wayne F. Reed, J. Appl. Polym. Sci., 13, 190-198, 2009. A stop-flow method is also described below.
2. General Background of the Invention
As polymers become more complex and sophisticated in architecture and composition, they gain the ability to perform more ‘intelligent’ functions than traditional polymers. The frontier of advanced polymeric materials in the 21st century will be dominated by these increasingly sophisticated polymers. The upcoming polymers can micellize, aggregate, and respond to stimuli, such as temperature, light, solvent polarity, different solvents and solvent mixtures, the presence of specific agents, metal ions, surfactants, multivalent ions, proteins, anti-bodies, receptors, etc. (see Langmuir (2007), 23, 1, 1-2; Polymer (2004), 45(2), 367-378; Macromolecular Chemistry II, University of Bayreuth, Bayreuth, Germany. Abstracts of Papers, 235th ACS National Meeting, New Orleans, La., United States, Apr. 6-10, 2008 (2008), POLY-599; Nano letters (2007), 7(1), 167-71; Journal of Materials Chemistry (2007), 17(38), 4015-4017; Langmuir, (1990), 6, 514-516; Macromolecules (2002), 35, 10182-10288; J. Phys. Chem. C (2007), 111, 8916-8924). The polymers and/or colloids may also undergo chemical reactions with other species.
Applications include sensing, encapsulation and release of agents (e.g. drugs, cosmetics, etc.), micropatterning, bioconjugated polymers for medical applications, self-healing, photosensitivity and/or electrically conductive properties for optical and electronics applications, photovoltaics etc. There is considerable interest in ‘fine tuning’ polymers to have well behaved stimuli responsiveness characteristics, interaction properties, specific phase behavior, etc.
Henceforth ‘stimuli responsiveness’ will be used to refer to one or more of the diverse types of behaviors that polymers and/or colloids can manifest, depending on their own structure, composition and other macromolecular and chemical characteristics, the conditions of their synthesis, and the details of the environment where they may be synthesized, transferred to, or otherwise used or applied. Such behaviors can include but are not limited to conformational changes, intra- and/or intermolecular micellization, intermolecular aggregation and/or supramolecular assemblage into organized structures, solubility, phase separation, ability to interact with other polymers or colloids or small molecules, such as metal ions, organic molecules, salts, surfactants, etc., ability to no longer interact with certain substances, ability to encapsulate and/or release drugs and other biologically active agents, lower critical solution temperature (LCST), color changes, and ability to react chemically with other species.
For example, polymers in solution can acquire stimuli responsiveness in sharp or gradual ways; e.g. LCST (lower critical solution temperature), micellization, aggregation, helix-coil, and other intra- and intermolecular transitions. Such transitions are of fundamental and applied interest. Fundamentally, they arise from the thermodynamics of complex, interacting systems. Whether sharp or gradual, these transitions, and stimuli responsiveness in general, depend on many factors, such as pH, ionic strength, solvent type and polarity, solvent mixture types, solvent chaotropicity or cosmotropicity, temperature, irradiation by electromagnetic waves, including light, and addition of interacting agents (e.g. small molecules, dyes, etc.), as well as the molecular weight and copolymeric composition and microstructure of the polymers themselves. Other examples concern the many types of associations that can take place between polymers and other polymers, micelles, emulsions, vesicles, liposomes, proteins, polypeptides, etc. These often involve formation of supramolecular (non-covalent) structures promoted by electrostatic, hydrophobic, depletion, and other forces.
Another very important application for the present invention is in the field of polymers derived from natural products. Because of the increasing demand for renewable sources for polymeric materials, as well as biodegradability and environmental concerns, there is a growing number of natural products that are being used for medicine, food, cosmetics, water treatment, oil recovery, composite materials, etc. These include, but are not limited to polysaccharides such as xanthans, alginates, cellulose derivatives, chitin derivatives, galactomannans, pectins, etc. as well as proteins and fibers. In order to make use of these natural products it is necessary to extract the desired agents, and then often modify them chemically, enzymatically, or by radiation, until desired characteristics are obtained, such as solubility in a given solvent (e.g. water), ability to interact with other substances (e.g. surfactants), achieve desired levels of viscosification, self-assemble into nano and microstructures, etc. The present invention will allow all of these processes-extraction, modification, and special properties- to be monitored. This will allow for optimization of the processes used in extracting, modifying, and deploying natural product derived polymers and colloids. The ability to monitor and control these steps is particularly important for natural products because the raw material, of vegetable or animal origins are normally highly variable in the content and characteristics of the desired materials to be extracted, which is a perennial problem for natural product manufacturers.
‘Polymer and/or colloid synthesis’ includes any type of reaction in which a polymer and/or colloid is produced or modified. An example of the latter is when a polymer is first made and then specific functional groups are attached to it, such as charge groups (e.g. sulfate, quaternary amines, carboxylate, etc.), oligomers, grafted polymers, etc. Other examples include the modifications made to polymers and/or colloids extracted from natural biological sources (e.g. plants, wood, seeds, fruits, etc.), as described above.
Traditional Methods for Relating Polymer Characteristics to their Stimuli Responsiveness.
These are time-consuming, cumbersome, and inefficient. They normally involve, even in modern high-throughput systems, the synthesis of a given end-product, or series of end-products, that are then subjected to various types of functionality characterization, and often also to standard polymer characterization methods. In many cases, the mere preparation of the endproduct can be disproportionately time-consuming, and require such steps as precipitation, purification, freeze-drying, re-dissolution, dialysis, etc., of the end-product. The usual ACOMP approach, (see W. F. Reed, U.S. Pat. No. 6,653,150, “Automatic mixing and dilution methods for online characterization of equilibrium and non-equilibrium properties of solutions containing polymers and/or colloids”; and A. M. Alb, M. F. Drenski, W. F. Reed, “Automatic continuous online monitoring of polymerization reactions (ACOMP)”, Polymer International, 57, 390-396, 2008) which has proven successful in a wide variety of contexts avoids these process steps by substituting ‘fluid-fluid’ sample handling. That is, the reactor fluid is continuously extracted, diluted with other fluids, and conditioned to produce a continuously measurable fluid sample of the reactor contents. No intermediate solid phase stages are normally used, and the often high levels of dilution (ranging up to dilution factors of many thousands) can even effectively change solvents by making the original solvent a tiny admixture to the dilution solvent. Such extraction/dilution/conditioning typically occurs on a time scale of tens of seconds to several minutes. The series of handling procedures in traditional methods can take hours, days, and even weeks.
The following references, and all references mentioned herein, are incorporated herein by reference:
Some additional bibliography showing LCST, micellization, bioconjugation, etc.:
    Macromolecular Chemistry II, University of Bayreuth, Bayreuth, Germany. Abstracts of Papers, 235th ACS National Meeting, New Orleans, La., United States, Apr. 6-10, 2008 (2008), POLY-599. Publisher: American Chemical Society, Washington, D.C.;    Abstracts of Papers, 233rd ACS National Meeting, Chicago, Ill., United States, Mar. 25-29, 2007 (2007);    Polymer (2003), 44(22), 6815-6823;    Polymer Preprints (American Chemical Society, Division of Polymer Chemistry) (2003), 44(1), 646-647;    Abstracts of Papers, 235th ACS National Meeting, New Orleans, La., United States, Apr. 6-10, 2008 (2008), POLY-596;    ACS Symposium Series (2008), 977 (Polymers for Biomedical Applications), 78-94. Publisher: American Chemical Society;    Soft Matter (2007), 3(6), 725-731;    Macromolecules (Washington, D.C., United States) (2007), 40(14), 4772-4779;    Abstracts of Papers, 231st ACS National Meeting, Atlanta, Ga., United States, Mar. 26-30, 2006 (2006), PMSE-224;    Macromolecules (1999), 32(21), 6917-6924;    Polymer Preprints (American Chemical Society, Division of Polymer Chemistry) (2002), 43(2), 969-970    PMSE Preprints (2002), 87 237-238. Publisher: American Chemical Society, CODEN: PPMRA9 ISSN: 1550-6703. Journal; Computer Optical Disk written in English.